6VZC

Tandem UU:GA mismatch within an RNA helix

Summary for 6VZC

• Entry DOI: 10.2210/pdb6vzc/pdb
• NMR Information: BMRB: 30730
• Descriptor: RNA 28-mer (1 entity in total)
• Functional Keywords: mismatch, internal loop, structural motif, ga base pair, uu base pair, rna
• Biological source: synthetic construct
• Total number of polymer chains: 1
• Total formula weight: 8963.33

Authors

Nikonowicz, E.P.,Chang, A.T. (deposition date: 2020-02-28, release date: 2020-09-02, Last modification date: 2024-05-15)

Primary citation

Chang, A.T.,Chen, L.,Song, L.,Zhang, S.,Nikonowicz, E.P.
2-Amino-1,3-benzothiazole-6-carboxamide Preferentially Binds the Tandem Mismatch Motif r(UY:GA).
Biochemistry, 59:3225-3234, 2020

PubMed Abstract: RNA helices are often punctuated with non-Watson-Crick features that may be targeted by chemical compounds, but progress toward identifying such compounds has been slow. We embedded a tandem UU:GA mismatch motif (5'-UG-3':5'-AU-3') within an RNA hairpin stem to identify compounds that bind the motif specifically. The three-dimensional structure of the RNA hairpin and its interaction with a small molecule identified through virtual screening are presented. The G-A mismatch forms a sheared pair upon which the U-U base pair stacks. The hydrogen bond configuration of the U-U pair involves O2 of the U adjacent to the G and O4 of the U adjacent to the A. The G-A and U-U pairs are flanked by A-U and G-C base pairs, respectively, and the stability of the mismatch is greater than when the motif is within the context of other flanking base pairs or when the 5'-3' orientation of the G-A and U-U pairs is swapped. Residual dipolar coupling constants were used to generate an ensemble of structures against which a virtual screen of 64480 small molecules was performed. The tandem mismatch was found to be specific for one compound, 2-amino-1,3-benzothiazole-6-carboxamide, which binds with moderate affinity but extends the motif to include the flanking A-U and G-C base pairs. The finding that the affinity for the UU:GA mismatch is dependent on flanking sequence emphasizes the importance of the motif context and potentially increases the number of small noncanonical features within RNA that can be specifically targeted by small molecules.

PubMed: 32786414
DOI: 10.1021/acs.biochem.0c00369

Experimental method

SOLUTION NMR